Although traditional synthetic polymer-drug conjugates provide many benefits over low molecular weight drugs, the molecular weight of synthetic polymer drug carriers (e.g., HPMA or PEG) is limited by the renal threshold. This results in fast elimination of the conjugate via glomerular filtration, low circulation time, and inefficient accumulation in tumor tissue by enhanced permeability and retention (EPR) effect.
Molecular weight and molecular weight distribution (MWD) of a drug carrier conjugate are crucial for effective functioning. The renal threshold limits the hydrodynamic radius of the conjugate to less than 45 Å. Thus, the molecular weight of polymeric carriers should be less than 30-40 kDa (the exact value depends on detailed structure). However, a decrease in molecular weight lowers the retention time of the conjugate in the circulatory system with concomitant decrease in pharmaceutical efficiency. An ideal drug carrier should possess a sufficiently high molecular weight to prevent rapid loss by glomerular filtration. High-molecular weight (long-circulating) polymer conjugates accumulate efficiently in tumor tissue due to the EPR effect. However, if they possess a nondegradable backbone, they may deposit and accumulate in various organs, impairing biocompatibility.